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Pediatric Neurology Oct 2021Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric...
BACKGROUND
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations.
METHODS
Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required.
RESULTS
Only two changes were made to clinical diagnostic criteria reported in 2013: "multiple cortical tubers and/or radial migration lines" replaced the more general term "cortical dysplasias," and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals.
CONCLUSIONS
Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.
Topics: Child; Consensus; Humans; Practice Guidelines as Topic; Tuberous Sclerosis
PubMed: 34399110
DOI: 10.1016/j.pediatrneurol.2021.07.011 -
Turkish Journal of Medical Sciences Nov 2020Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder that is characterized by cellular and tissue dysplasia in several organs. With the advent... (Review)
Review
Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder that is characterized by cellular and tissue dysplasia in several organs. With the advent of genetic and molecular techniques, mutations in the TSC1 or TSC2 genes were discovered to be responsible for mTOR overactivation, which is the underlying mechanism of pathogenesis. TSC is a highly heterogenous clinical entity with variable presentations and severity of disease. The brain, heart, skin, eyes, kidneys, and lungs are commonly involved in this syndrome, with neurologic symptoms comprising a significant source of morbidity and mortality. In 2012, the diagnostic criteria for TSC were revised by the International Tuberous Sclerosis Complex Consensus panel, and genetic testing was incorporated into the guidelines. Early detection of cardiac rhabdomyomas or TSC-associated skin lesions can suggest the diagnosis and underlie the importance of clinical vigilance. Animal studies have demonstrated the benefit of using mTOR inhibitors for various symptoms of TSC, and they have been successfully translated into clinical trials with significant improvement in symptom burden. Subependymal giant cell astrocytomas, renal angiomyolipomas, and epilepsy are the three FDA-approved indications in relation to TSC for the use of everolimus, which is a first generation mTOR inhibitor. Rapamycin has been FDA approved for lymphangioleiomyomatosis. Other TSC symptoms that could potentially benefit from this class of medication are currently under investigation. TSC constitutes a unique combination of protean physical symptoms and neurobehavioral abnormalities. TSC associated neuropsychiatric disorders (TAND), including intellectual disability, mood disorders, and autism spectrum disorder, represent significant challenges but remain underdiagnosed and undertreated. The TAND checklist is a useful tool for routine use in the clinical evaluation of TSC patients. A multidisciplinary treatment plan, based on the specific problems and needs of individuals, is the key to management of this genetic condition. Ongoing research studies have been providing promising leads for developing novel mechanistic strategies to address the pathophysiology of TSC.
Topics: Animals; Brain; Epilepsy; Humans; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein
PubMed: 32222129
DOI: 10.3906/sag-2002-133 -
Brain : a Journal of Neurology Jul 2023Epileptogenesis in infants with tuberous sclerosis complex (TSC) is a gradual and dynamic process, leading to early onset and difficult-to-treat seizures. Several... (Review)
Review
Epileptogenesis in infants with tuberous sclerosis complex (TSC) is a gradual and dynamic process, leading to early onset and difficult-to-treat seizures. Several cellular, molecular and pathophysiologic mechanisms, including mammalian target of rapamycin (mTOR) dysregulation, GABAergic dysfunction and abnormal connectivity, may play a role in this epileptogenic process and may also contribute to the associated developmental encephalopathy. Disease-specific antiseizure medications or drugs targeting the mTOR pathway have proved to be effective in TSC-associated epilepsy. Pre-symptomatic administration of vigabatrin, a GABAergic drug, delays seizure onset and reduces the risk of a subsequent epileptic encephalopathy, such as infantile spasms syndrome or Lennox-Gastaut syndrome. Everolimus, a rapamycin-derived mTOR inhibitor, reduces seizure frequency, especially in younger patients. This evidence suggests that everolimus should be considered early in the course of epilepsy. Future trials are needed to optimize the use of everolimus and determine whether earlier correction of mTOR dysregulation can prevent progression to developmental and epileptic encephalopathies or mitigate their severity in infants with TSC. Clinical trials of several other potential antiseizure drugs (cannabidiol and ganaxolone) that target contributing mechanisms are also underway. This review provides an overview of the different biological mechanisms occurring in parallel and interacting throughout the life course, even beyond the epileptogenic process, in individuals with TSC. These complexities highlight the challenges faced in preventing and treating TSC-related developmental and epileptic encephalopathy.
Topics: Infant; Humans; Everolimus; Tuberous Sclerosis; Epilepsy; Seizures; Sirolimus; TOR Serine-Threonine Kinases; Anticonvulsants
PubMed: 36806388
DOI: 10.1093/brain/awad048 -
Cell Feb 2021Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that...
Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.
Topics: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cytoplasmic Granules; DNA Helicases; Evolution, Molecular; Female; Humans; Insulin; Lysosomal Membrane Proteins; Lysosomes; Mechanistic Target of Rapamycin Complex 1; Neurons; Phenotype; Poly-ADP-Ribose Binding Proteins; RNA Helicases; RNA Recognition Motif Proteins; RNA-Binding Proteins; Rats, Wistar; Signal Transduction; Tuberous Sclerosis; Zebrafish; Rats
PubMed: 33497611
DOI: 10.1016/j.cell.2020.12.024 -
Science Advances Feb 2022Tuberous sclerosis complex subunit 1 () and 2 () are frequently mutated in non-small cell lung cancer (NSCLC), however, their effects on antitumor immunity remained...
Tuberous sclerosis complex subunit 1 () and 2 () are frequently mutated in non-small cell lung cancer (NSCLC), however, their effects on antitumor immunity remained unexplored. A CRISPR screening in murine / (KP) model identified and as potent regulators of programmed cell death ligand 1 (Pd-l1) expression in vitro and sensitivity to anti-programmed cell death receptor 1 (PD-1) treatment in vivo. or knockout (KO) promoted the transcriptional and membrane expression of PD-L1 in cell lines. -deficient tumors manifested an inflamed microenvironment in patient samples and The Cancer Genome Atlas dataset. In syngeneic murine models, KP--KO tumors showed notable response to anti-PD-1 antibody treatment, but -wild-type tumors did not. Patients with /-mutant NSCLC receiving immune checkpoint blockade (ICB) had increased durable clinical benefit and survival. Collectively, / loss defines a distinct subtype of NSCLC characterized as inflamed tumor microenvironment and superior sensitivity to ICB.
Topics: Animals; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Mice; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Microenvironment
PubMed: 35119931
DOI: 10.1126/sciadv.abi9533 -
Annals of Neurology Feb 2021Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants.
METHODS
In this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open-label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure.
RESULTS
In 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty-seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223-535) vs 124 days (95% CI = 33-149); OLT: 426 days (95% CI = 258-628) vs 106 days (95% CI = 11-149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug-resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p < 0.001). No adverse events related to preventive treatment were noted.
INTERPRETATION
Preventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2021;89:304-314.
Topics: Anticonvulsants; Drug Resistant Epilepsy; Electroencephalography; Epilepsy; Female; Humans; Infant; Infant, Newborn; Male; Mass Screening; Seizures; Spasms, Infantile; Tuberous Sclerosis; Vigabatrin
PubMed: 33180985
DOI: 10.1002/ana.25956 -
JAMA Neurology Mar 2021Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC).
OBJECTIVE
To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC.
DESIGN, SETTING, AND PARTICIPANTS
This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medication-resistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication.
INTERVENTIONS
Patients received oral cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks.
MAIN OUTCOMES AND MEASURES
The prespecified primary outcome was the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period.
RESULTS
Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6% (95% CI, 40.4%-55.8%) for the CBD25 group, 47.5% (95% CI, 39.0%-54.8%) for the CBD50 group, and 26.5% (95% CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95% CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5% (95% CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo.
CONCLUSIONS AND RELEVANCE
Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02544763.
Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Diarrhea; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Infant; Internationality; Male; Middle Aged; Seizures; Sleepiness; Treatment Outcome; Tuberous Sclerosis; Young Adult
PubMed: 33346789
DOI: 10.1001/jamaneurol.2020.4607 -
Science (New York, N.Y.) Jan 2022Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are...
Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are responsible for malformations of cortical development (MCDs), which result in developmental delay and epilepsy in children. We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells. In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying potential treatment options for TSC and related disorders. The identification of CLIP cells reveals the extended interneuron generation in the human brain as a vulnerability for disease. In addition, this work demonstrates that analyzing MCDs can reveal fundamental insights into human-specific aspects of brain development.
Topics: Brain; Brain Neoplasms; Carcinogenesis; Cell Lineage; Cell Proliferation; Disease Progression; ErbB Receptors; Gene Expression Profiling; Humans; Induced Pluripotent Stem Cells; Interneurons; Loss of Heterozygosity; Neural Stem Cells; Organoids; RNA-Seq; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein
PubMed: 35084981
DOI: 10.1126/science.abf5546 -
Epilepsia Feb 2022To evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open-label... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open-label extension (OLE) of the randomized, placebo-controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported.
METHODS
Patients who completed the randomized trial enrolled to receive CBD (Epidiolex in the United States; Epidyolex in the EU; 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC-associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC).
RESULTS
Of 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1-57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One-year retention rate was 79%. Median treatment time was 267 days (range, 18-910) at a 27 mg/kg/day mean modal dose. Most patients (92%) had an adverse event (AE). Most common AEs were diarrhea (42%), seizure (22%), and decreased appetite (20%). AEs led to permanent discontinuation in 6% of patients. There was one death that was deemed treatment unrelated by the investigator. Elevated liver transaminases occurred in 17 patients (9%) patients; 12 were taking valproate. Median percentage reductions in seizure frequency (12-week windows across 48 weeks) were 54%-68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%-61%, 29%-45%, and 6%-11% across 12-week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks.
SIGNIFICANCE
In patients with TSC, long-term add-on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement.
Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Humans; Infant; Middle Aged; Seizures; Treatment Outcome; Tuberous Sclerosis; Young Adult
PubMed: 34957550
DOI: 10.1111/epi.17150